The broader goal of our studies is to understand how epithelia react to damage and in particular the role of the biliary epithelium in the repair and regeneration of the liver. Diseases of the intrahepatic biliary tree ("cholangiopathies") are severe chronic debilitating liver diseases affecting the pediatric and young adult population. Polycystic liver diseases, a group of genetic cholangiopathies, are characterized by progressive cystic dilations of the biliary epithelium that may cause complications requiring liver transplantation. These diseases are of particular scientific interest because of their association with an altered function of proteins localized on the primary cilia. Adult Dominant Polycystic Kidney Disease (ADPKD) is caused by genetically transmitted defect in polycystin-1 or -2. These proteins function as mechanoceptors, and are involved in signaling pathways that regulate also cell differentiation and epithelial morphogenesis. Epithelial angiogenic signaling, particularly VEGF and Angiopoietin-1, were shown to be upregulated in biliary epithelial cells (cholangiocytes) from ADPKD and may play a role in the pathogenesis of liver disease. The hypothesis addressed in this proposal is that autocrine and paracrine angiogenic signals originating from the biliary epithelium are one of the mechanisms responsible for liver cysts growth and disease progression in ADPKD. This hypothesis will be tested trough three specific aims: 1) to examine the relationships between genetic defects and up-regulation of angiogenic signaling in the biliary epithelium of ADPKD patients; 2) to study the intracellular pathways involved in autocrine VEGF- and angiopoieting-1 mediated stimulation of cholangiocyte growth and survival; 3) To study if blockade of angiogenic signaling reduces liver cysts growth in vivo in ADPKD mouse models. These questions will be addressed in vitro and in vivo using mice with conditional inactivation of polycystin-1 or polycystin 2. These studies will a) increase our understanding of VEGF regulation and signaling in secretory epithelia, b) better clarify the role of VEGF/angiopoietin signaling in liver diseases c) provide important information on mechanisms leading to the progressive growth of cysts in ADPKD d) provide an important proof of concept for the role anti-angiogenic therapy to control the growth of liver and kidney cysts in ADPKD. [unreadable] [unreadable] Public Health Relevance: Polycystic liver diseases are a group of inherited conditions characterized by an abnormal development of the cells that line the bile ducts. This leads to the formation of multiple biliary microhamartomas that progressively dilate to macroscopic cysts, scattered throughout the liver. Although liver function is usually preserved in these disorders, severe cyst complications (mass effect, hemorrhage, infection or rupture) may develop and require urgent liver transplantation, since no forms of medical treatment are currently available to prevent biliary cyst enlargement. Stimulation of the growth of bile duct cells by angiogenic growth factors aberrantly overexpressed in these disorders may be responsible for the cyst enlargement that leads to the severe complications of the liver disease. In this application we aim to use animals with genetic defects that reproduce this disease in order to understand its cause and to develop new ways to treat its complications. Specifically, we will test antiangiogenic strategies. It is expected that therapeutic strategies devised for the liver may also be effective in the kidney, functional impairment of which contributes to morbidity in these patients. Moreover, the ability to block progression of the disease would not only benefit these patients but could spare organs for transplantation of others. [unreadable] [unreadable] [unreadable]